The prototypic second messenger cyclic AMP (cAMP) regulates a myriad of important biological processes under both physiological and pathological conditions, including cancer, diabetes, heart failure, inflammation and neurological disorders. Hence, it is not surprising that current pharmaceutical medications target the cAMP signaling pathway more than any other pathway. In multi-cellular eukaryotic organisms, the effects of cAMP are mainly transduced by two ubiquitously-expressed intracellular cAMP receptors, the classic protein kinase A/cAMP-dependent protein kinase (PKA/cAPK) and the more recently discovered exchange proteins directly activated by cAMP/cAMP-regulated guanine nucleotide exchange factor (Epac/cAMP-GEF). As a major intracellular receptor of cAMP, the important roles that Epac proteins play in normal physiological functions and diseases are now increasingly appreciated. To date, most functional analyses of Epac proteins have been performed under in vitro settings. To bridge this gap, we will interrogate the biological functions of Epac1 in physiological setting using tissue-specific Epac1 knockout mouse models and test the potential of Epac1 as a therapeutic target using novel Epac specific inhibitors. The proposed research is based on more than a decade of extensive studies of the Epac-mediated signaling performed in our laboratory and directly builds on a several recent novel developments in the lab including the characterization of global Epac1 null mice and the discovery of first-in-class Epac specific inhibitors. The combination of new genetic animal models and small molecule probes will enable us to reveal much desired in vivo functions of Epac1, to develop new pharmacological tools for investigating Epac-mediated cell signaling and disease mechanisms, which may eventually lead to novel mechanism-based therapeutic strategies for leptin resistance/obesity.